Combination treatments for opioid crisis

ABSTRACT

A method of reducing the risk of medication-related overdose, death, or other injury associated with inappropriate consumption of alcohol in conjunction with prescription opioid analgesics, comprising: administering a combination medication having an effective amount of one or more opioid medications, and an effective amount of one or more aldehyde dehydrogenase inhibitors, in order to provide the powerful analgesic effects of the opioid in conjunction with a substance that prevents concomitant alcohol consumption, thereby reducing the risk of alcohol mediated opioid overdose or death. A combination medication, including an effective amount of one or more opioid medications, and an effective amount of one or more aldehyde dehydrogenase inhibitors and a pharmaceutically acceptable carrier.

FIELD OF THE DISCLOSURE

The present disclosure relates to methods for reducing the risk ofmedication-related overdose, death, or other injury associated withinappropriate consumption of alcohol in conjunction with prescriptionopioid analgesics.

BACKGROUND

Opioid analgesics (e.g., morphine, methadone, hydrocodone, oxycodone,hydromorphone, fentanyl, oxymorphone, codeine, etc.) are one of the mostwidely abused classes of prescription medications. These medications areknown to be dangerous, and put users at risk for adverse health effects,among the most concerning of which are the complications of overdose,including death. These risks are increased exponentially when themedications are misused, such as when taken along with alcohol.

Excessive alcohol consumption also accounts for a significant healthburden, and is common among groups that report high rates ofprescription drug abuse. And when taken with opioids, it iswell-established that alcohol increases central nervous systemdepression and the risk for overdose. Despite these known risks,patients exhibit very high rates of non-adherence with medicalrecommendations to avoid alcohol consumption when taking opioidmedications. In fact, per estimates from the National Institute of DrugAbuse (NIDA), roughly 21-29% of patients prescribed opioids for chronicpain misuse them, and a large proportion of this misuse relates toco-administration of these medications with alcohol.

To quantify alcohol involvement in opioid medication-related deaths, andto inform prevention efforts, the U.S. Center for Disease Control andPrevention (CDC) recently analyzed data for drug-related deaths thatinvolved opioids and alcohol in 13 states. The analysis showed thatalcohol was involved in 22.1% of opioid drug-related deaths. These dataare highly consistent with an analysis which evaluated the prevalenceand characteristics of opioid-related deaths involving alcohol inOntario, Canada, which showed that approximately 20% of fatal opioidoverdoses involved alcohol. Similarly, another recent analysis showedthat Americans with chronic non-cancer pain managed with opioids and aprevious diagnosis of alcohol abuse or dependence had 5 times the rateof opioid overdose, 2.3 times the rate of accidents, and 1.2 times therate of injury, as well as higher all-cause health care costs.

Based on these and other data, the CDC recently concluded thatinterventions to reduce the abuse of alcohol in conjunction with opioidmedications are needed. However, the current standard of care forprevention of co-administration of alcohol with opioids is limited topatient counseling and random urine drug testing, which as evidenced bythe data outlined above, represents an ineffective measure. A moredefinitive solution for preventing co-administration of alcohol withopioid medications is therefore essential for enhancing the safety ofthese inherently dangerous medications.

SUMMARY

Disclosed is a method of reducing the chances of alcohol mediated opioidoverdose or death. In embodiments, the method includes administering acombination medication, for example as a single pill, that includes aneffective amount of one or more opioid medications, and an effectiveamount of one or more aldehyde dehydrogenase inhibitors, in order toprovide the powerful analgesic effects of the opioid in conjunction witha substance that prevents concomitant alcohol consumption, therebyreducing the risk of alcohol mediated opioid overdose or death.

Also disclosed is a combination medication that includes an effectiveamount of one or more opioid medications, and an effective amount of oneor more aldehyde dehydrogenase inhibitors and a pharmaceuticallyacceptable carrier.

In embodiments, the aldehyde dehydrogenase inhibitor includes one ormore of disulfiram, calcium carbimide, coprine, cyanamide,1-aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonylureas, metronidazole, ampal, benomyl, citral and active isomers thereof,chloral hydrate, chlorpropamide analogs NPI-1 and API-1, CVT-10216,DEAB, gossypol, kynurenine tryptophan metabolites, molinate,nitroglycerin, pargyline, active metabolites, analogs, orpharmaceutically acceptable salts thereof. In specific examples, thealdehyde dehydrogenase inhibitor comprises, consists essentially, orconsists of disulfiram, active disulfiram metabolites and/orpharmaceutically acceptable salts thereof. In embodiments, the aldehydedehydrogenase inhibitor consists essentially of disulfiram, activemetabolites and/or pharmaceutically acceptable salts thereof.

In embodiments, the one or more opioid medications comprises one or moreprescription opioid analgesics. In embodiments, the one or more opioidmedications comprises one or more of alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,sufentanil, tilidine, and tramadol. In specific examples, the one ormore opioid medications comprises, consists essentially of, or consistsof morphine, methadone, hydrocodone, oxycodone, oxymorphone,hydromorphone, fentanyl, or codeine.

DETAILED DESCRIPTION

Unless otherwise explained, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the disclosed subject matter belongs.Definitions of common terms in chemistry terms may be found in TheMcGraw-Hill Dictionary of Chemical Terms, 1985, and The CondensedChemical Dictionary, 1981.

As used herein, the singular terms “a,” “an,” and “the” include pluralreferents unless context clearly indicates otherwise. Similarly, theword “or” is intended to include “and” unless the context clearlyindicates otherwise. Also, as used herein, the term “comprises” means“includes.” Hence “comprising A or B” means including A, B, or A and B.Except as otherwise noted, any quantitative values are approximatewhether the word “about” or “approximately” or the like are stated ornot. The materials, methods, and examples described herein areillustrative only and not intended to be limiting. Any molecular weightor molecular mass values are approximate and are provided only fordescription.

Except as otherwise noted, the methods and techniques of the presentdisclosure are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbookof Practical Organic Chemistry, Including Qualitative Organic Analysis,Fourth Edition, New York: Longman, 1978.

In case of conflict, the present specification, including explanationsof terms, will control.

To facilitate review of the various embodiments of this disclosure, thefollowing explanations of specific terms are provided:

Administration: To provide or give a subject a composition, such as apharmaceutical composition including an aldehyde dehydrogenase inhibitorand an opioid medication, by any effective route. Exemplary routes ofadministration include, but are not limited to, injection (such assubcutaneous, intramuscular, intradermal, intraperitoneal (ip), andintravenous (iv)), oral, sublingual, transdermal, and inhalation routes.

Aldehyde dehydrogenases: Enzymes of enzyme class (EC) 1.2.1.3 thatcatalyze the oxidation of aldehyde.

Aldehyde dehydrogenase inhibitor: An inhibitor of the enzymatic activityof an aldehyde dehydrogenase. Examples of aldehyde dehydrogenaseinhibitors include: disulfiram([1-diethylthiocarbamoyldisulfanyl-N,N-diethylmethanethioamide]) andactive metabolites thereof, such as S-methyl N,N-diethyldithiocarbamate,S-methyl N,N-diethyldithiocarbamate sulfoxide, and S-methylN,N-diethylthiocarbamate sulfoxide; calcium carbimide, sold as thecitrate salt under the trade name Temposil®; coprine and activemetabolites thereof, such as 1-amino cyclopropanol; cyanamide and activemetabolites thereof, such as HNO; 1-aminocyclopropanol and activemetabolites thereof, such as ACP; daidzin; cephalosporins; antidiabeticsulfonyl ureas; metronidazole; ampal and active metabolites thereof,such as thioampal; benomyl (methyl[1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamate) and activemetabolites thereof, such as MBT; citral and active isomers thereof,such as neral and geranial; chloral hydrate; chlorpropamide analogsNPI-1 and API-1, CVT-10216, DEAB, gossypol, kynurenine tryptophanmetabolites KA, 3-HK, and 3-HAA; molinate and active metabolitesthereof, such as molinate sulfoxide and molinate sulfone; nitroglycerinand active metabolites thereof, such as NO₃; pargyline and activemetabolites thereof, such as propiolaldehyde; and any other metabolitesor analogs exhibiting aldehyde dehydrogenase inhibiting activity.

Contacting: Placement in direct physical association including both insolid or liquid form. Contacting can occur in vivo, for example byadministering an agent to a subject.

Inhibiting or treating a disease or a condition: Inhibiting the fulldevelopment of a disease or condition, for example, in a subject who isin need of an opioid, such as a subject undergoing pain managementtreatment. “Treatment” refers to a therapeutic intervention thatameliorates a sign or symptom of a disease or pathological conditionafter it has begun to develop. The term “ameliorating,” with referenceto a disease or pathological condition, refers to any observablebeneficial effect of the treatment. The beneficial effect can beevidenced, for example, by a delayed onset of clinical symptoms of thedisease in a susceptible subject, a reduction in severity of some or allclinical symptoms of the disease, such as pain, a slower progression ofthe disease, an improvement in the overall health or well-being of thesubject, or by other clinical or physiological parameters associatedwith a particular disease. A “prophylactic” treatment is a treatmentadministered to a subject who does not exhibit signs of a disease orexhibits only early signs for the purpose of decreasing the risk ofdeveloping pathology.

Inhibit: To reduce to a measurable extent. For example, to reduce theincident or chance of alcohol mediated or exacerbated opioid induceddeath and/or overdose.

Opioid medication: Drugs whose primary mode of action is to bind toopioid receptors in the brain, spinal cord, and other areas of the body.Opioid medications work to reduce feelings of pain. Prescription opioidsare powerful pain-reducing medications that include prescriptionoxycodone, hydrocodone and morphine, among others, and have bothbenefits as well as potentially serious risks. These medications canhelp manage pain when prescribed for the right condition and when usedproperly. But when misused or abused, for example when taken inconjunction with alcohol, they can cause serious harm, includingoverdose and death. Examples of opioid medications include alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, sufentanil, tilidine, tramadol, mixtures of any of theforegoing, salts of any of the foregoing, and the like.

Pharmaceutically acceptable carriers: The pharmaceutically acceptablecarriers of use are conventional. Remington's Pharmaceutical Sciences,by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995,describes compositions and formulations suitable for pharmaceuticaldelivery of the compositions disclosed herein.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. For solid compositions (such as powder, pill, tablet, orcapsule forms), conventional non-toxic solid carriers can include, forexample, pharmaceutical grades of mannitol, lactose, starch, ormagnesium stearate. In addition to biologically neutral carriers,pharmaceutical compositions to be administered can contain minor amountsof non-toxic auxiliary substances, such as wetting or emulsifyingagents, preservatives, and pH buffering agents and the like, for examplesodium acetate or sorbitan monolaurate.

Subject: The term “subject” includes both human and veterinary subjects,for example, humans, non-human primates, dogs, cats, horses, rats, mice,and cows. Similarly the term mammal includes both human and non-humanmammals. In some embodiments, a subject is a patient, such as patientprescribed one or more opioid medications.

Therapeutic agent or Pharmaceutical agent: A chemical compound, smallmolecule, or other composition capable of inducing a desired therapeuticor prophylactic effect when properly administered to a subject, forexample reducing the chances of alcohol-related opioid death and/oroverdose.

Therapeutically effective amount or Effective amount: The amount ofagent, such as an aldehyde dehydrogenase inhibitor and an opioidmedication, that is sufficient to prevent, treat (includingprophylaxis), reduce and/or ameliorate the symptoms and/or underlyingcauses of any of a disorder or disease, for example to treat, prevent,inhibit, and/or reduce chances of alcohol mediated opioid death and/oroverdose.

Suitable methods and materials for the practice or testing of thisdisclosure are described below. Such methods and materials areillustrative only and are not intended to be limiting. Other methods andmaterials similar or equivalent to those described herein can be used.For example, conventional methods well known in the art to which thisdisclosure pertains are described in various general and more specificreferences. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

Overview

Opioids are involved in more overdose deaths than any other drug class.The Centers for Disease Control (CDC) estimates that in 2015 alone,there were over 22,000 deaths involving prescription opioids, equivalentto about 62 deaths per day, and the death rate and rate of othercomplications associated with opioid overdose have continued to rise ata rapid pace. The risk of opioid overdose is increased exponentiallywhen these medications are misused, such as when taken along withalcohol, as co-consumption of alcohol with opioids results in asynergistic degree of central nervous system and respiratory depression.Despite these known risks, patients exhibit very high rates ofnon-adherence with medical recommendations to avoid alcohol consumptionwhen taking opioid medications.

Per estimates from the National Institute of Drug Abuse (NIDA), roughly21-29% of patients prescribed opioids for chronic pain misuse them, anda large proportion of this misuse relates to co-administration of thesemedications with alcohol. To quantify alcohol involvement in opioidmedication-related deaths, the U.S. CDC recently analyzed data fordrug-related deaths that involved opioids and alcohol in 13 states,which showed that alcohol was involved in 22.1% of opioid drug-relateddeaths. These data are highly consistent with a recent analysis whichevaluated the prevalence and characteristics of opioid-related deathsinvolving alcohol in Ontario, Canada, which showed that approximately20% of fatal opioid overdoses involved alcohol.

In conjunction with the CDC estimates of prescription opioid-relatedoverdose deaths referenced above, these figures suggest thatco-consumption of alcohol with prescription opioid medication accountsfor nearly 5,000 deaths annually, or more than 13 deaths every day inthe United States.

Similarly, another recent analysis showed that Americans with chronicnon-cancer pain managed with opioids and a previous diagnosis of alcoholabuse or dependence had 5 times the rate of opioid overdose, 2.3 timesthe rate of accidents, and 1.2 times the rate of injury, as well ashigher all-cause health care costs.

Based on these and other data, the CDC recently concluded thatinterventions to reduce the abuse of alcohol in conjunction with opioidmedications are needed. However, the current standard of care forprevention of co-administration of alcohol with opioids is limited topatient counseling and random urine drug testing, which as evidenced bythe data outlined above, represents an ineffective measure.

A more definitive solution for preventing co-administration of alcoholwith opioid medications is therefore essential for enhancing the safetyof these inherently dangerous medications. The present disclosureaddresses the need to prevent co-administration of alcohol withprescription opioids.

Methods of Treatment

Disclosed herein is a method of reducing the chances of alcohol mediatedopioid death and/or overdose. The disclosed method involves combining analdehyde dehydrogenase inhibitor (e.g., disulfiram[1-diethylthiocarbamoyldisulfanyl-N, N-diethylmethanethioamide]) into acombination medication, such as a ‘poly-pill’, with a prescribed opioid,for example with each of the eight most commonly prescribed opioid painmedication (e.g., hydrocodone, oxycodone, morphine, methadone, codeine,fentanyl, hydromorphone, and oxymorphone) and administering thiscombination to a subject, such a subject prescribed the opioidmedication. Administration of such as combination would enable thedelivery of effective opioid-derived analgesia in a manner whichprevents co-consumption of alcohol, so as to reduce the risk ofalcohol-mediated opioid overdose and/or death.

Existing pharmacotherapies for treating alcoholism includeadministration of agents that inhibit the enzyme aldehyde dehydrogenase(ALDH), which is involved in the removal of acetaldehyde, a toxicmetabolite of alcohol. Although multiple forms of ALDH exist. ALDH-I andALDH-II are the major enzymes responsible for the oxidation ofacetaldehyde. While not being bound by theory, ALDH-I has a higheraffinity for acetaldehyde than ALDH-II, and is believed to be theprimary enzyme involved in alcohol detoxification. The combination, suchas in a poly-pill, of the aldehyde dehydrogenase inhibitor with aprescribed opioid will prevent the co-consumption of alcohol withprescribed opioid medications, because disulfiram and other aldehydedehydrogenase inhibitors prevent the metabolism of alcohol. Therefore,once an opioid-aldehyde dehydrogenase inhibitor combination medicationis administered, the opioid will induce its typical profile of intendedanalgesic effects, but any subsequent co-consumption of alcohol willresult in a strong noxious physiologic reaction to the alcohol.

The disclosed method includes providing and/or administering to asubject a pharmaceutical preparation that includes an effective amountof one or more opioid medications and an effective amount of one or morealdehyde dehydrogenase inhibitors, thereby reducing the chances of thesubject succumbing to alcohol mediated opioid death and/or overdose. Inembodiments, the method includes the administration of an aldehydedehydrogenase inhibitor. Examples of aldehyde dehydrogenase inhibitorsinclude, e.g., disulfiram, calcium carbimide, coprine, cyanamide,1-aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonylureas, metronidazole, ampal, benomyl, citral and active isomers thereof,chloral hydrate, chlorpropamide analogs NPI-1 and API-1, CVT-10216,DEAB, gossypol, kynurenine tryptophan metabolites, molinate,nitroglycerin, pargyline and any active metabolites or analogsexhibiting aldehyde dehydrogenase inhibiting activity.

Patients who consume such inhibitors of ALDH experience mild to severediscomfort if they ingest alcohol. Disulfiram, the best known aldehydedehydrogenase inhibitor and sold under the tradenames Cronetal™,Abstenil™ Stopetyl™, Contrain™, Antadix™, Anietanol™, Exhoran™,Antabuse™, Etabuse™, Abstinyl™ Thiuranide™, Esperal™, Tetradine™ Noxal™,Tetraeti™, is a potent irreversible inhibitor of ALDH-II that slightlyinhibits ALDH-I. Ingestion of alcohol while taking disulfiram and otheraldehyde dehydrogenase inhibitors results in the accumulation ofaldehydes, which causes tachycardia, flushing, diaphoresis, dyspnea,nausea and vomiting (also known collectively as the disulfiram ordisulfiram-ethanol reaction). Disulfiram consumption producessensitivity to alcohol which results in a highly unpleasant reactionwhen the subject ingests even small amounts of alcohol. Thus, inspecific embodiments, the dehydrogenase inhibitor comprises, consistsessentially of, or consists of disulfiram.

In specific embodiments, the method includes the administration of oneor more of disulfiram, calcium carbimide, coprine, cyanamide,1-aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonylureas, metronidazole, ampal, benomyl, citral and active isomers thereof,chloral hydrate, chlorpropamide analogs NPI-1 and API-1, CVT-10216,DEAB, gossypol, kynurenine tryptophan metabolites, molinate,nitroglycerin, pargyline, and/or any active metabolites or analogsexhibiting aldehyde dehydrogenase inhibiting activity. In specificembodiments, the method includes the administration of one or more ofdisulfiram and/or active metabolites thereof, such as S-methylN,N-diethyldithiocarbamate, S-methyl N,N-diethyldithiocarbamatesulfoxide, and S-methyl N,N-diethylthiocarbamate sulfoxide.

As disclosed herein the method includes the administration of an opioidmedication, such as one or more prescription opioid analgesics. Opioidmedications within the present disclosure include, but are not limitedto, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium,oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, sufentanil, tilidine, tramadol,mixtures of any of the foregoing, salts of any of the foregoing. Thus,in embodiments, a subject is administered a therapeutically effectiveamount of one or more of alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, desomorphine, dextromoramide, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, sufentanil, tilidine,tramadol, and salts thereof. In embodiments, the subject is notadministered propoxyphene, for example propoxyphene is specificallyexcluded from the combination medication disclosed herein. In specificembodiments, the one or more opioid medications comprises, consistsessentially of, or consists of morphine, methadone, hydrocodone,oxycodone, fentanyl, or codeine.

In certain embodiments, the subject is prescribed one or more opioidmedications for the management of chronic pain. In certain embodiments,the subject is prescribed one or more opioid medications for themanagement of acute pain. In certain embodiments, the subject isprescribed one or more opioid medications for the treatment of opioidaddiction. In certain embodiments, the subject is prescribed one or moreopioid medications for the management of refractory restless legssyndrome or chronic cough.

Therapeutic Formulations

Aspects of the present disclosure further concern a combinationmedication that includes an aldehyde dehydrogenase inhibitor and anopioid medication.

In embodiments, the combination medication includes an effective amountof one or more aldehyde dehydrogenase inhibitors. In embodiments, theone or more aldehyde dehydrogenase inhibitors is selected from one ormore of disulfiram, calcium carbimide, coprine, cyanamide,1-aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonylureas, metronidazole, ampal, benomyl, citral and active isomers thereof,chloral hydrate, chlorpropamide analogs NPI-1 and API-1, CVT-10216,DEAB, gossypol, kynurenine tryptophan metabolites, molinate,nitroglycerin, pargyline and any active metabolites or analogsexhibiting aldehyde dehydrogenase inhibiting activity. In specificembodiments, the dehydrogenase inhibitor comprises, consists essentiallyof, or consists of one or more of disulfiram and/or active metabolitesthereof, such as S-methyl N,N-diethyldithiocarbamate, S-methylN,N-diethyldithiocarbamate sulfoxide, and S-methylN,N-diethylthiocarbamate sulfoxide. In specific embodiments, thedehydrogenase inhibitor comprises, consists essentially of, or consistsof disulfiram.

In embodiments, the one or more opioid medications included in thecombination medication is selected from alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,sufentanil, tilidine, tramadol, mixtures of any of the foregoing, saltsof any of the foregoing, and the like. In embodiments, the combinationmedication does not include propoxyphene, for example propoxyphene isspecifically excluded from the combination medication. In specificembodiments, the one or more opioid medications comprises, consistsessentially of, or consists of morphine, methadone, hydrocodone,oxycodone, fentanyl, or codeine.

The method of treatment and pharmaceutical formulations of the presentdisclosure may further include one or more drugs in addition to theopioid medication and the aldehyde dehydrogenase inhibitor, whichadditional drug(s) may or may not act synergistically therewith. Thus,in certain embodiments, a combination of two or more opioid medicationsmay be included in the formulation, in addition to the aldehydedehydrogenase inhibitor. For example, the dosage form may include opioidmedications having different properties, such as half-life, solubility,potency, and a combination of any of the foregoing. In yet furtherembodiments, one or more opioid aldehyde dehydrogenase inhibitors isincluded and a further non-opioid drug is also included, in addition tothe opioid medication. In certain embodiments, such non-opioid drugswould preferably provide additional analgesia, and include, for example,aspirin; acetaminophen; non-sterioidal antiinflammatory drugs(“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate(NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphanor dextrorphan, or ketamine; cycooxygenase-II inhibitors (“COX-IIinhibitors”); and/or glycine receptor antagonists. Other examplesinclude naloxone (used either to minimize opioid-induced constipationfor chronic opioid users or as an abuse-deterrent, to prevent theinjection and snorting of oxycodone).

Suitable non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zido-metacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Useful dosages of these drugs are well known tothose skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, d-methadone or pharmaceutically acceptable saltsthereof. For purposes of the present disclosure, the term “NMDAantagonist” is also deemed to encompass drugs that block a majorintracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM₁ or GT_(1b) a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838, and to treat chronicpain in U.S. Pat. No. 5,502,058.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680. COX-2 inhibitors have been reported in the art andmany chemical structures are known to produce inhibition ofcyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S.Pat. Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752;5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368;5,436,265; 5,409,944; and 5,130,311. Certain preferred COX-2 inhibitorsinclude celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam,6-methoxy-2 naphthylacetic acid (6-MNA), MK-966, nabumetone (prodrug for6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinationsthereof. Dosage levels of COX-2 inhibitor on the order of from about0.005 mg to about 140 mg per kilogram of body weight per day aretherapeutically effective in combination with an opioid analgesic.Alternatively, about 0.25 mg to about 7 g per patient per day of a COX-2inhibitor is administered in combination with an opioid medication.

The dosage form of a disclosed pharmaceutical composition will bedetermined by the mode of administration chosen. For example, inaddition to injectable fluids, oral dosage forms may be employed. Oralformulations may be liquid such as syrups, solutions or suspensions orsolid such as powders, pills, tablets, or capsules. Methods of preparingsuch dosage forms are known, or will be apparent, to those skilled inthe art.

In embodiments the combination medication is an oral dosage. The oraldosage forms of the disclosure comprise a therapeutically effectiveamount of an opioid medication, together with an aldehyde dehydrogenaseinhibitor, in a therapeutically effective amount that provides anegative, “aversive” physical experience when alcohol is taken inconjunction with the oral dosage form.

The combination of the opioid medication, together with an aldehydedehydrogenase inhibitor can be employed in admixtures with conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for oral administration, known to the art.Suitable pharmaceutically acceptable carriers include but are notlimited to water, salt solutions, alcohols, gum arabic, vegetable oils,benzyl alcohols, polyethylene glycols, gelate, carbohydrates such aslactose, amylose or starch, magnesium stearate talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure buffers, coloring, flavoring and/oraromatic substances and the like. They can also be combined wheredesired with other active agents, for example other analgesic agents.For oral administration, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from inert, non-toxic pharmaceutically excipients whichare suitable for the manufacture of tablets. Such excipients include,for example an inert diluent such as lactose; granulating anddisintegrating agents such as cornstarch; binding agents such as starch;and lubricating agents such as magnesium stearate. In tablet form, thetablets may be uncoated or they may be coated by known techniques forelegance or to delay release of the active ingredients. Formulations fororal use may also be presented as hard gelatin capsules wherein theactive ingredient is mixed with an inert diluent.

Aqueous suspensions contain the above-identified combinations typicallyinclude one or more excipients suitable as suspending agents, forexample pharmaceutically acceptable synthetic gums such ashydroxypropylmethylcellulose or natural gums. Oily suspensions may beformulated by suspending the above-identified combinations in avegetable oil or mineral oil. The oily suspensions may contain athickening agent such as beeswax or cetyl alcohol. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

An oral dosage form according to the disclosure may be provided as, forexample, granules, spheroids, beads, pellets (hereinafter collectivelyreferred to as “multiparticulates”). An amount of the multiparticulateswhich is effective to provide the desired dose of opioid over time maybe placed in a capsule or may be incorporated in any other suitable oralsolid form. Alternatively, the oral dosage form may be in the form of atablet.

Certain embodiments of the pharmaceutical compositions comprising anopioid medication and an aldehyde dehydrogenase inhibitor may beformulated in unit dosage form suitable for individual administration ofprecise dosages. The amount of active ingredient such as an opioidmedication and an aldehyde dehydrogenase inhibitor administered willdepend on the subject being treated, the severity of the disorder, andthe manner of administration, and is known to those skilled in the art.Within these bounds, the formulation to be administered will contain aquantity of the opioid medication and the aldehyde dehydrogenaseinhibitor in an amount effective to achieve the desired effect in thesubject being treated.

In particular examples, for oral administration the compositions areprovided in the form of a tablet or capsule containing from about 25 mgto 500 mg of the aldehyde dehydrogenase inhibitor (e.g., disulfiram),particularly about 25 mg, about 50 mg, about 75 mg, about 100 mg, about200 mg, about 250 mg, or about 500 mg of the active ingredient, incombination with the dose of the selected opioid necessary to provideanalgesia. This range of doses of disulfiram was selected to facilitateachieving a total daily dose of disulfiram between 250 mg and 500 mg andallow for wide variability in the frequency of the opioid dosingschedules (e.g., the opioid medication can be taken between one and sixtimes daily). In one exemplary oral dosage regimen, a tablet containingabout 100 mg of disulfiram in combination with 20 mg of oxycodone isadministered every 6 hours (i.e., four times a day), thereby providing atypical total daily dose of disulfiram of about 400 mg. Typical dosageforms of the most common opioid medications (e.g., hydrocodone oroxycodone) are formulated as 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, or 160mg. Thus combinations of opioid medication with various doses ofdisulfiram, for example between 25 mg and 500 mg to allow flexibilitywith regard to the frequency of opioid dosing, are contemplated. Thusfor example, in the patient who occasionally takes a single pain tableton an as-needed basis or who takes a single long-acting opioid tablet ona daily basis, that opioid would be combined with either 250 mg or 500mg disulfiram. In another patient who takes the opioid analgesic morefrequently (e.g., 2-6 times/day), it would be combined with a range ofbetween about 50 mg and about 250 mg disulfiram (e.g., 50, 100, 150,200, 250 mg), in order to achieve a total daily dose of disulfiramgenerally between 250 mg and 500 mg. Disulfiram suits this need forflexibility in treating a range of chronic pain patients because it canbe administered in a once-daily or a multiple-times daily manner andstill be effective for the entire day. Thus, in embodiments, thedisulfiram dose is selected which, when the pain medication is taken inthe prescribed manner, results in the delivery of a total daily dose of250-500 mg disulfiram.

In particular examples, for oral administration the compositions areprovided in the form of a tablet or capsule containing from about 1.0 toabout 200 mg of the opioid medication, particularly about 2.0 mg, about2.5 mg, 5 mg, about 10 mg, about 20, about, about 50 mg, about 75, about100, about 125, about 150, about 175 or about 200 mg of the opioidmedication (depending on the potency of the particular opioid selected),which for the symptomatic adjustment of the dosage to the subject beingtreated. In one exemplary oral dosage regimen, a tablet containing fromabout 1 mg to about 200 mg (such as about 5 mg to about 160 mg) opioidmedication is administered between one and six times a day, such as onetime, two times, three times, four times, five times, or six timesdaily.

Single or multiple administrations of the composition comprising theopioid medication, together with an aldehyde dehydrogenase inhibitor canbe carried out with dose levels and pattern being selected by thetreating physician. Generally, multiple doses are administered. Inparticular examples, the composition is administered once per day, twiceper day, three times per day, four times per day, five times per day,six times per day, every other day, twice a week, weekly, or monthly.Treatment will typically continue for at least a month, more often fortwo or three months, sometimes for six months or a year, and may evencontinue indefinitely, i.e., chronically. Repeat courses of treatmentare also possible.

Routes of administration useful in the disclosed methods include but arenot limited to oral and parenteral routes, such as intravenous (iv),intraperitoneal (ip), rectal, topical, ophthalmic, nasal, andtransdermal. Pharmaceutical compositions including opioid medication andan aldehyde dehydrogenase inhibitor can be administered to subjects by avariety of routes. These include oral, nasal (such as intranasal),ocular, buccal, enteral, intravitreal, or other mucosal (such as rectalor vaginal) or topical administration. Alternatively, administrationwill be by orthotopic, intradermal subcutaneous, intramuscular,parenteral intraperitoneal, or intravenous injection routes. Suchpharmaceutical compositions are usually administered as pharmaceuticallyacceptable compositions that include physiologically acceptablecarriers, buffers or other excipients.

An effective amount of an opioid medication and an aldehydedehydrogenase inhibitor will depend, at least, on the particular methodof use, and the manner of administration of the therapeutic composition.A “therapeutically effective amount” of a composition is a quantity of aspecified compound sufficient to achieve a desired effect in a subjectbeing treated. Ideally, a therapeutically effective amount of analdehyde dehydrogenase inhibitor is an amount sufficient to cause asubject to forgo alcohol without a substantial side effect in thesubject. Similarly, a therapeutically effective amount of an opioidmedication is an amount sufficient to cause the desired effect, such isthe prevention of pain without a substantial side effect in the subject.

The specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factors,including the activity of the specific compound, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex and diet of the subject, mode and time of administration,rate of excretion, drug combination, and severity of the condition ofthe subject undergoing therapy.

Typically, preparation of a pharmaceutical composition (for example, foruse as a medicament or in the manufacture of a medicament) entailspreparing a pharmaceutical composition that is essentially free ofpyrogens, as well as any other impurities that could be harmful tohumans or animals. The opioid medication and an aldehyde dehydrogenaseinhibitor may be included in pharmaceutical compositions (includingtherapeutic and prophylactic formulations), which are typically combinedtogether with one or more pharmaceutically acceptable vehicles orcarriers and, optionally, other therapeutic ingredients.

To formulate the pharmaceutical compositions, the opioid medication andthe aldehyde dehydrogenase inhibitor can be combined with variouspharmaceutically acceptable additives, as well as a base or vehicle fordispersion of the compound. Desired additives include, but are notlimited to, pH control agents, such as arginine, sodium hydroxide,glycine, hydrochloric acid, citric acid, and the like. In addition,local anesthetics (for example, benzyl alcohol), isotonizing agents (forexample, sodium chloride, mannitol, sorbitol), adsorption inhibitors(for example, Tween 80), solubility enhancing agents (for example,cyclodextrins and derivatives thereof), stabilizers (for example, serumalbumin), and reducing agents (for example, glutathione) can beincluded. When the composition is a liquid, the tonicity of theformulation, as measured with reference to the tonicity of 0.9% (w/v)physiological saline solution taken as unity, is typically adjusted to avalue at which no substantial, irreversible tissue damage will beinduced at the site of administration. Generally, the tonicity of thesolution is adjusted to a value of about 0.3 to about 3.0, such as about0.5 to about 2.0, or about 0.8 to about 1.7.

The opioid medication and the aldehyde dehydrogenase inhibitor can bedispersed in a base or vehicle, which can include a hydrophilic compoundhaving a capacity to disperse the compound, and any desired additives.The base can be selected from a wide range of suitable compounds,including but not limited to, copolymers of polycarboxylic acids orsalts thereof, carboxylic anhydrides (for example, maleic anhydride)with other monomers (for example, methyl (meth)acrylate, acrylic acidand the like), hydrophilic vinyl polymers, such as polyvinyl acetate,polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, such ashydroxymethylcellulose, hydroxypropylcellulose and the like, and naturalpolymers, such as chitosan, collagen, sodium alginate, gelatin,hyaluronic acid, and nontoxic metal salts thereof. Often, abiodegradable polymer is selected as a base or vehicle, for example,polylactic acid, poly(lactic acid-glycolic acid) copolymer,polyhydroxybutyric acid, poly (hydroxybutyric acid-glycolic acid)copolymer and mixtures thereof. Alternatively or additionally, syntheticfatty acid esters such as polyglycerin fatty acid esters, sucrose fattyacid esters and the like can be employed as vehicles. Hydrophilicpolymers and other vehicles can be used alone or in combination, andenhanced structural integrity can be imparted to the vehicle by partialcrystallization, ionic bonding, cross-linking and the like. The vehiclecan be provided in a variety of forms, including fluid or viscoussolutions, gels, pastes, powders, and microspheres.

The opioid medication and the aldehyde dehydrogenase inhibitor can becombined with the base or vehicle according to a variety of methods, andrelease of the compound can be by diffusion, disintegration of thevehicle, or associated formation of water channels. In somecircumstances, the compound is dispersed in microcapsules (microspheres)or nanocapsules (nanospheres) prepared from a suitable polymer, forexample, isobutyl 2-cyanoacrylate (see, for example, Michael et al., J.Pharmacy Pharmacol. 43: 1-5, 1991), and dispersed in a biocompatibledispersing medium, which yields sustained delivery and biologicalactivity over a protracted time.

The opioid medication and aldehyde dehydrogenase inhibitor canalternatively contain as pharmaceutically acceptable vehicles substancesas required to approximate physiological conditions, such as pHadjusting and buffering agents, tonicity adjusting agents, wettingagents and the like, for example, sodium acetate, sodium lactate, sodiumchloride, potassium chloride, calcium chloride, sorbitan monolaurate,and triethanolamine oleate. For solid compositions, conventionalnontoxic pharmaceutically acceptable vehicles can be used which include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talcum, cellulose, glucose,sucrose, magnesium carbonate, and the like.

Pharmaceutical compositions for administering the opioid medication andthe aldehyde dehydrogenase inhibitor can be also be formulated as asolution, microemulsion, or other ordered structure suitable for highconcentration of active ingredients. The vehicle can be a solvent ordispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, liquid polyethylene glycol, and thelike), and suitable mixtures thereof. Proper fluidity for solutions canbe maintained, for example, by the use of a coating such as lecithin, bythe maintenance of a desired particle size in the case of dispersibleformulations, and by the use of surfactants. In many cases, it will bedesirable to include isotonic agents, for example, sugars, polyalcohols,such as mannitol and sorbitol, or sodium chloride in the composition.Prolonged absorption of the compound can be brought about by includingin the composition an agent which delays absorption, for example,monostearate salts and gelatin.

For prophylactic and therapeutic purposes, the pharmaceuticalcompositions can be administered to the subject in a single bolusdelivery, via continuous delivery (for example, continuous transdermal,mucosal or intravenous delivery) over an extended time period, or in arepeated administration protocol (for example, by an hourly, daily orweekly, repeated administration protocol). The therapeutically effectivedosage of the compound can be provided as repeated doses within aprolonged prophylaxis or treatment regimen that will yield clinicallysignificant results to alleviate one or more symptoms or detectableconditions associated with a targeted disease or condition as set forthherein.

Therapeutic compositions that include an opioid medication and analdehyde dehydrogenase inhibitor can be delivered by way of a pump (seeLanger, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201, 1987;Buchwald et al, Surgery 88:507, 1980; Saudek et al, N. Engl. J. Med.321:574, 1989) or by continuous subcutaneous infusions, for example,using a mini-pump. An intravenous bag solution can also be employed. Onefactor in selecting an appropriate dose is the result obtained, asmeasured by the methods disclosed here, as are deemed appropriate by thepractitioner. Other controlled release systems are discussed in Langer(Science 249: 1527-33, 1990).

In one example, a pump is implanted (for example see U.S. Pat. Nos.6,436,091; 5,939,380; and 5,993,414). Implantable drug infusion devicesare used to provide patients with a constant and long-term dosage orinfusion of a therapeutic agent. Such device can be categorized aseither active or passive.

Active drug or programmable infusion devices feature a pump or ametering system to deliver the agent into the patient's system. Anexample of such an active infusion device currently available is theMedtronic SYNCHRO MED™ programmable pump. Passive infusion devices, incontrast, do not feature a pump, but rather rely upon a pressurized drugreservoir to deliver the agent of interest. An example of such a deviceincludes the Medtronic ISOMED™.

In particular examples, therapeutic compositions are administered bysustained-release systems. Suitable examples of sustained-releasesystems include suitable polymeric materials (such as, semi-permeablepolymer matrices in the form of shaped articles, for example films, ormirocapsules), suitable hydrophobic materials (for example as anemulsion in an acceptable oil) or ion exchange resins, and sparinglysoluble derivatives (such as, for example, a sparingly soluble salt).Sustained-release compositions can be administered orally, parenterally,intracistemally, intraperitoneally, topically (as by powders, ointments,gels, drops or transdermal patch), or as an oral or nasal spray.Sustained-release matrices include polylactides (U.S. Pat. No.3,773,919, EP 58,481), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al, Biopolymers 22:547-556, 1983,poly(2-hydroxyethyl methacrylate)); (Langer et al., J. Biomed. Mater.Res. 15: 167-277, 1981; Langer, Chem. Tech. 12:98-105, 1982, ethylenevinyl acetate (Langer et al., Id.) or poly-D-(−)-3-hydroxybutyric acid(EP 133,988).

Polymers can be used for ion-controlled release. Various degradable andnondegradable polymeric matrices for use in controlled drug delivery areknown in the art. In specific examples, the opioid medication and thealdehyde dehydrogenase inhibitor are contained in a time released and/ortamper proof pill and/or capsule. Example or such capsule formulationsare well known in the art and include those formulations sold under thetradename OxyContin® and the like. Examples of such time releaseformulations can be found for example in U.S. Pat. Nos. 5,478,577;5,681,585, 5,672,360; 5,958,459; 6,103,261; 6,143,332; 5,965,161;5,958,452, 5,968,551, 5,681,585, 5,811,126, 5,843,480, 5,681,585,5,811,126, 5,843,480, 5,849,240, 5,866,164, 5,879,705, 5,891,471,5,914,131, 5,965,163, 5,968,551, 6,103,261, 6,143,322, 6,245,357,6,261,599, 6,294,195. 6,419,960, 6,696,066, 7,514,100, 7,514,100,7,829,120, 7,846,476, 7,988,998, 8,071,119, 8,075,872, 8,114,383,8,114,384, 8,153,149, 8,153,152, 8,153,661, 8,168,217, 8,192,722,8,231,898, 8,309,060, 8,323,889, 8,354,124, 8,361,499, 8,362,029,8,372,432, 8,414,919, 8,415,401, 8,420,056, 8,420,120, 8,445,018,8,486,448, 8,486,449, 8,487,002, 8,529,948, 8,551,520, 8,597,681,8,609,683, 8,647,667, 8,653,066, 8,658,631, 8,668,929,8,685,447,8,691,270, 8,715,721, 8,722,086, 8,728,522, 8,741,885, 8,753,665,8,765,178, 8,795,723, 8,808,740, 8,808,745, 8,815,289, 8,821,929,8,834,925, 8,846,072, 8,846,086, 8,858,963, 8,871,265, 8,877,241,8,894,987, 8,894,988, 8,911,719, 8,920,833, 8,920,834, 8,927,013,8,927,014, 8,927,025, 8,937,097, 8,945,614, 8,951,555, 8,951,556,8,956,644, 8,962,019, 8,974,821, 8,980,291, 8,987,291, 8,999,961,9,023,394, 9,023,401, 9,034,376, 9,040,084, 9,044,402, 9,050,335,9,056,052, 9,056,107, 9,060,940, 9,060,976, 9,084,816, 9,095,614,9,095,615, 9,101,661, 9,132,096, 9,149,533, 9,161,917, 9,198,861,9,198,863, 9,198,867, 9,205,055, 9,205,056, 9,216,176, 9,226,901,9,226,907, 9,233,073, 9,233,160, 9,278,074, 9,278,083, 9,289,391,9,308,170, 9,308,171, 9,320,717, 9,387,174, 9,387,177, 9,393,206,9,393,207, 9,399,022, 9,402,813, 9,427,407, 9,433,582, 9,433,625,9,439,866, 9,452,163, 9,456,985, 9,468,636, 9,486,412, 9,486,413,9,486,451, 9,492,389, 9,492,390, 9,492,391, 9,492,392, 9,492,393,9,498,444, 9,498,456, 9,504,681, 9,517,207, 9,517,236, 9,517,271,9,526,704, 9,526,724, 9,539,328, 9,545,380, 9,545,448, 9,555,113,9,572,779, 9,572,803, 9,572,804, 9,572,805, 9,572,885, 9,579,285,9,579,389, 9,592,204, 9,616,030, 9,616,055, 9,629,807, 9,629,837,9,636,303, 9,642,809, 9,655,853, 9,655,861, 9,655,893, 9,655,894,9,655,971, 9,662,326, 9,662,399, 9,669,022, 9,669,023, 9,669,024,9,675,581, 9,675,610, 9,675,611, 9,682,077, 9,693,961, 9,694,080,9,707,179, 9,707,180, 9,707,224, 9,713,611, 9,730,885, 9,737,490,9,744,136, 9,744,151, 9,750,701, 9,750,703, 9,750,736, 9,757,341,9,757,371, 9,763,886, 9,763,933, 9,770,416, 9,770,417, 9,775,808,9,775,809, 9,775,810, 9,775,811, 9,775,812, 9,775,837, 9,789,104, and9,789,105.

The subject matter of the present disclosure is further illustrated bythe following non-limiting Examples.

EXAMPLES

This example describes exemplary methodology (clinical trial) fortesting the efficacy of the disclosed opioid medication aldehydedehydrogenase inhibitor combination.

A clinical trial is instituted to demonstrate that the combinationtherapy 1) remains effective as an analgesic and 2) effectively preventsco-administration of alcohol while the patient is using an opioidanalgesic (for example, within 12-24 hours following administration ofthe last dose of the combination medication).

The following represents one of the possible clinical trials that may beinstituted to determine efficacy of the combination medication andmethods of treatment disclosed herein.

1. Eligibility Assessment and Enrollment

-   -   a. Inclusion Criteria        -   i. An individual with a chronic pain condition treated with            an opioid analgesic.        -   ii. The individual has a prior history of alcohol abuse or            is suspected of non-adherence with recommendations to avoid            concomitant alcohol consumption while taking opioid            medication.        -   iii. Age greater than 18 years        -   iv. Adults must be able to understand and sign the informed            consent document        -   v. Patients must have an ECOG performance score of 0-2.        -   vi. Patients must have laboratory and physical examination            parameters within acceptable limits by standard of practice            guidelines.    -   b. Exclusion criteria        -   Comorbid alcohol dependency (active, not in remission), or            opioid use disorder (active, not in remission).    -   c. Patient registration        -   Patients will be registered on the trial by the principal            investigator or their designee using a protocol specific            registration form after signing the appropriate informed            consent or agreeing by assent.

2. Study Implementation

-   -   This is a prospective study of the efficacy of the combination        of an aldehyde dehydrogenase inhibitor, such as disulfiram, and        an opioid medication. As both classes of drugs have proven        individual efficacy at achieving the desired clinical outcome        when administered individually, toxicity studies would be        unnecessary. In an example, the study would include 3 groups        plus a control: traditional opioid, traditional disulfiram and a        comparable opioid-disulfiram combination. Pharmacokinetics would        also be performed, as there may need to be some adjustment (for        example lowering) in the dosing of certain opioids because their        metabolism may be slowed by the disulfiram. Patients are asked        to complete a pain rating daily or multiple times per day and        are advised/counseled on the importance of alcohol avoidance        when taking the pain medication. They are selected/notified        randomly at multiple intervals throughout the trial (1-3×/wk)        that they must provide a urine or blood sample, and complete        surveys regarding their consumption of alcohol during the trial.        The groups are then compared for safety and efficacy (in terms        of both analgesia and prevention of alcohol co-consumption),        side effect profile, and the like.

3. Study Evaluation

-   -   Patients will undergo the following evaluations which may be        performed within 4 weeks of enrollment:        -   Detailed History and Physical Examination including, vital            signs, ECOG status, demographic information and family            history.        -   Laboratory evaluations: CBC with differential; Chem 20            [Sodium (Na), Potassium (K), Chloride (CI), Total C02            (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN),            Albumin, Calcium total, Magnesium total (Mg), Inorganic            Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total            Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK,            Uric Acid]; PT/PTT; Blood alcohol concentration; Urine drug            screen (with quantitative and qualitative opioid analyses).

4. Follow-Up Examinations

-   -   Patients following evaluations:    -   a. physical exam to include vital signs and ECOG status;    -   b. laboratory evaluations: pharmacokinetic analysis of aldehyde        dehydrogenase inhibitor and opioid medication.    -   c. Patients are asked to complete a pain rating daily or        multiple times per day    -   d. Patients are advised/counseled on the importance of alcohol        avoidance when taking the pain medication.    -   e. Patients are required to provide urine samples and/or other        samples needed to determine blood-alcohol levels at random        intervals    -   f. Patients complete a survey/questionnaire about their recent        level of alcohol consumption at multiple points over the course        of the study.    -   g. Patients agree to inform study investigators if they        experience a complication associated with opioid overdose at any        point over the course of the study.

5. Data Collection

-   -   Data prior to and during the course of the patient's        participation will be collected in order to monitor patient        eligibility, and will include review of medical and family        history records, blood work, and urinary studies.    -   a. Toxicity Criteria: This study will utilize the Common        Terminology Criteria for Adverse Events (CTCAE) version 4 for        toxicity and adverse event reporting. CTCAE version 4 is        available on the World Wide Web at ctep.info.nih.gov. All        appropriate treatment areas should have access to a copy of the        CTCAE version 4.    -   b. Statistical Considerations: A primary objective of this study        is to determine the efficacy of the combination medication to        provide the desired opioid effect while reducing the incidence        of co-consumption with alcohol.

6. Rationale for Subject Selection

Subjects will be selected for this protocol based on chronic paincondition managed with opioids and alcohol abuse or non-adherence withrecommendations to avoid alcohol consumption while taking opioidmedication.

7. Data Reporting

-   -   a. Routine Data Reporting: All details of patient evaluation,        management and treatment will be documented in the patient        medical record. The following information may be captured on the        CRFs: detailed demographic information including family history;        and laboratory results).    -   b. Serious Adverse Event Reporting Requirements: The following        events will be reported: all deaths with the exception of those        due to progressive disease; all events that are not listed in        the consent form and that are possibly, probably or definitely        related to the research; all serious adverse events (SAEs) that        are not listed in the consent form, but are possibly, probably        or definitely related to the research (with the exception of        death due to progressive disease). An SAE is defined as an        untoward medical occurrence that: resulted in death; was        life-threatening; required or prolonged hospitalization; caused        persistent or significant disability/incapacity; resulted in        congenital anomalies or birth defects; or required intervention        to prevent permanent impairment or death.    -   c. Adverse Event Reporting in the Continuing Review Report: The        following events will be presented to provide the information        necessary to clearly identify risks to participants and to make        a risk:benefit determination: all Grade 2 events that are not in        the consent form, but are possibly, probably or definitely        related to the research; all Grade 3 and 4 events that are        possibly, probably or definitely related to the research; all        Grade 5 events regardless of attribution; and all Serious Events        regardless of attribution.

Although certain embodiments have been illustrated and described herein,it will be appreciated by those of ordinary skill in the art that a widevariety of alternate and/or equivalent embodiments or implementationscalculated to achieve the same purposes may be substituted for theembodiments shown and described without departing from the scope. Thosewith skill in the art will readily appreciate that embodiments may beimplemented in a very wide variety of ways. This application is intendedto cover any adaptations or variations of the embodiments discussedherein. Therefore, it is manifestly intended that embodiments be limitedonly by the claims and the equivalents thereof.

What is claimed is:
 1. A method of reducing the chances of alcoholmediated opioid overdose or death during maintenance therapy formanagement of pain, comprising: selecting a subject for maintenancetherapy for management of pain; administering a single composition tothe subject, comprising: an effective amount of one or more opioidmedications for the management of pain; and an effective amount of oneor more aldehyde dehydrogenase inhibitors sufficient to prevent alcoholconsumption, the one or more aldehyde dehydrogenase inhibitors selectedfrom disulfiram, calcium carbimide, coprine, cyanamide,1-aminocyclopropanol, daidzin, cephalosporins, antidiabetic sulfonylureas, metronidazole, ampal, benomyl, citral and active isomers thereof,chloral hydrate, chlorpropamide analogs,(benzoyloxy)[4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethylester (NPI-1),4-chloro-N-ethyl-N-[(propylamino)carbonyl]benzenesulfonamid (API-1),3-(((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl)benzoicacid (CVT-10216), N,N-diethylaminobenzaldehyde (DEAB), gossypol,molinate, nitroglycerin, pargyline, or pharmaceutically acceptable saltsthereof, enabling provision of the powerful analgesic effects of theopioid in a manner which prevents concomitant alcohol consumption,thereby reducing the risk of alcohol mediated opioid overdose or deathduring maintenance therapy for management of pain.
 2. The method ofclaim 1, wherein the aldehyde dehydrogenase inhibitor is disulfiram, oran pharmaceutically acceptable salts thereof.
 3. The method of claim 1,wherein the aldehyde dehydrogenase inhibitor is disulfiram, orpharmaceutically acceptable salts thereof.
 4. The method of claim 1,wherein the one or more opioid medications is one or more prescriptionopioid analgesics.
 5. The method of claim 1, wherein the one or moreopioid medications comprises one or more of alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, butorphanol,clonitazene, codeine, desomorphine, dextromoramide, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, metopon, morphine,myrophine, narceine, nicomorphine, norlevorphanol, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, sufentanil, tilidine, and tramadol.
 6. The method of claim5, wherein the one or more opioid medications is morphine, methadone,hydrocodone, oxycodone, hydromorphone, fentanyl, or codeine.
 7. Themethod of claim 6, wherein the one or more opioid medications consistsessentially of one or more of morphine, methadone, hydrocodone,hydromorphone, oxycodone, fentanyl, or codeine.
 8. The method of claim1, wherein the subject is prescribed one or more opioid medications forthe management of chronic pain.
 9. The method of claim 1, wherein thesubject is prescribed one or more opioid medications for the managementof acute pain.
 10. A method of reducing the chances of alcohol mediatedopioid overdose or death during maintenance therapy for management ofpain, comprising: selecting a subject for maintenance therapy formanagement of pain; administering in a single dose a single combinationmedication, comprising: an effective amount of an opioid medication forthe management of pain selected from alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, butorphanol,clonitazene, codeine, desomorphine, dextromoramide, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, metopon, morphine,myrophine, narceine, nicomorphine, norlevorphanol, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, sufentanil, tilidine, and tramadol; and an effective amountof one or more aldehyde dehydrogenase inhibitors selected fromdisulfiram, calcium carbimide, coprine, cyanamide, 1-aminocyclopropanol,daidzin, cephalosporins, antidiabetic sulfonyl ureas, metronidazole,ampal, benomyl, citral and active isomers thereof, chloral hydrate,chlorpropamide analogs, (benzoyloxy)[4-chlorophenyl)sulfonyl]carbamicacid 1,1-dimethylethyl ester (NPI-1),4-chloro-N-ethyl-N-[(propylamino)carbonyl]benzenesulfonamid (API-1),3-(((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl)benzoicacid (CVT-10216), N,N-diethylaminobenzaldehyde (DEAB), gossypol,molinate, nitroglycerin, pargyline, or pharmaceutically acceptable saltsthereof, enabling provision of the powerful analgesic effects of theopioid in a manner which prevents concomitant alcohol consumption,thereby reducing the risk of alcohol mediated opioid overdose or deathduring maintenance therapy for management of chronic pain.
 11. Themethod of claim 10, wherein the aldehyde dehydrogenase inhibitor isdisulfiram, or a pharmaceutically acceptable salts thereof.
 12. Themethod of claim 10 wherein the aldehyde dehydrogenase inhibitor consistsessentially of disulfiram, or pharmaceutically acceptable salts thereof.13. The method of claim 10, wherein the one or more opioid medicationscomprises morphine, hydrocodone, oxycodone, hydromorphone, fentanyl, orcodeine.
 14. The method of claim 13, wherein the one or more opioidmedications consists essentially of one or more of morphine,hydrocodone, hydromorphone, oxycodone, fentanyl, or codeine.
 15. Themethod of claim 10, wherein the subject is prescribed one or more opioidmedications for the management of chronic pain.
 16. The method of claim10, wherein the subject is prescribed one or more opioid medications forthe management of acute pain.